D-Cycloserine (“DCS”) has long been clinically approved and used as an antibiotic to treat tuberculosis.
Studies in rats showed that DCS could facilitate the psychological process of extinction learning (“extinction”), which led Davis et al. to postulate that DCS could be useful in the treatment of anxiety disorders and other related disorders (see U.S. patent application Ser. No. 10/473,640). Unlike traditional anti-anxiety drugs that are administered on a chronic basis and address physiological symptoms of anxiety, DCS is effective because it facilitates the process of extinction when used on an achronic basis in conjunction with psychotherapy.
Extinction is perhaps most easily explained by referencing the famous studies of Pavlov, who trained dogs to salivate at the sound of a bell by pairing the bell with food. What happens when one continues to ring the bell, but stops bringing the food? Eventually, the dog will stop salivating, and that process is called extinction. The extinction process is often very important in psychotherapy. For example, a returning Iraqi war veteran with post-traumatic stress disorder (PTSD) might feel tremendous stress when driving a car through city streets, a person with acrophobia might feel extreme anxiety when going up in a glass-paneled elevator, and an individual with obsessive-compulsive disorder might feel the need to wash his hands many times after shaking hands with another individual. The goal of psychotherapy for such patients is to extinguish these undesirable responses through an extinction training process, analogous to extinguishing the salivation response in Pavlov's dogs. For example, if an individual with obsessive-compulsive disorder who fears shaking hands with others, based on worries about getting sick, undergoes an extinction training program of shaking hands with many strangers, and does not become sick as a result, then that individual's fear of shaking hands will likely be reduced.
The first human clinical trial demonstrating that DCS could be used in conjunction with extinction training to effectively treat anxiety disorders is described by Davis et al. in U.S. patent application Ser. No. 10/924,591. In this placebo-controlled clinical study, subjects were administered DCS prior to virtual reality therapy sessions for treatment of acrophobia (fear of heights), leading to a significant reduction in the number of therapy sessions required to reach a defined clinical endpoint.
Subsequent human clinical studies, pairing administration of DCS with extinction training for treatment of various anxiety disorders, including social anxiety disorder, panic disorder, and obsessive-compulsive disorder, have further demonstrated that DCS can facilitate the psychological process of extinction and therefore increase the efficacy of extinction training. A meta-analysis covering both animal and human studies has recently been published by Norberg et al. (“A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy”, Biological Psychiatry, (2008) 63, pp. 1118-1126). In the three-sentence summary of the results in the Abstract section, Norberg et al. state: “D-cycloserine was more effective when administered a limited number of times and when given immediately before or after extinction training/exposure therapy.”
In each of the human clinical studies that are described in the meta-analysis, DCS was administered prior to extinction training. DCS is routinely administered to subjects prior to extinction training events such as cognitive behavioral therapy sessions, typically thirty minutes to three hours prior to the extinction training. It also may be administered after extinction training. For example, McDevitt (U.S. patent application Ser. No. 11/347,937) teaches a method wherein DCS is administered to a patient following extinction training only if the extinction training is deemed to have gone well.
It has been proposed that DCS acts by consolidating extinction learning, rather than or in addition to impacting the acquisition of extinction learning. Ledgerwood et al. (“Effects of D-Cycloserine on Extinction of Conditioned Freezing”, Behavioral Neuroscience, (2003) 117, pp. 341-349) tested this approach in model studies with rats by injecting DCS after extinction training. The results showed that post-extinction training administration of DCS also facilitated extinction learning (as did pre-extinction training administration of DCS), and that the extent of this facilitatory effect decreased as the length of time between extinction training and administration was increased, with no significant facilitatory effect found when the delay between extinction training and administration of DCS was increased to four hours.
Irrespective of whether the main positive impact of DCS on extinction learning derives from improving acquisition or improving consolidation, administering DCS in advance of extinction training has been the preferred approach in the expensive and extensive human clinical trials that have been performed in which DCS is administered on an achronic basis in conjunction with extinction training. DCS has a significant half-life in the body, and by administering DCS prior to extinction training, therapeutically effective levels of DCS can be obtained both during extinction training (during the acquisition of extinction learning phase) and after extinction training (during the consolidation of extinction learning phase).
Accordingly, the current state of the art in using DCS to facilitate extinction training is to administer the drug on an achronic basis sometime prior to extinction training, although there is also evidence that administering DCS immediately after extinction training may also be effective. This practice has been demonstrated to be effective in a number of human clinical trials, and can provide a significant improvement in therapeutic outcomes relative to extinction training alone. However, this practice may not reap all the benefits that administration of DCS can provide, since it neglects the opportunity to take advantage of the fact that certain types of learning are consolidated during sleep. For example, Stickgold and Walker (“Sleep-dependent memory consolidation and reconsolidation”, Sleep Medicine (2007)8, pp. 331-343) describe numerous types of learning for which the primary consolidation of learning occurs during sleep.
By administering DCS prior to or immediately following, for example, a therapy session during typical working hours, the benefits of DCS upon consolidation of learning are unlikely to be maximized during the portion of the 24-hour cycle (i.e., the sleeping portion) when some of the most effective consolidation of learning takes place. There is a need for improved methods of administering DCS compositions such that DCS can more effectively facilitate consolidation of learning during sleep.